Any inflammation that occurs in the mammalian body is the clinical result of a sequence of events known as the arachidonic acid (ARA) cascade. Cell membranes consist of phospholipids. including fatty acids, one of which is ARA. In the inflammation process, the first step is the release of ARA from the phospholipid. The next step is the conversion of ARA into the specific mediator of inflammation. One pathway is the cyclooxygenase and the other is called the lipoxygenase pathway. Cortisone, along with other selected steroidal agents. block both inflammation pathways by inhibiting ARA release.
The mode of action of HEPES-ester is thought to be at the level of leukotrienes B4, but it is also possible that it occurs at higher levels in the inflammatory cascade, perhaps at the phospholipase A2 (PPLA2). Inhibition of PPLA2 action would arrest the aforedescribed cascade effect from being initiated.
Medical science looks for other biochemicals that lack the recognized side effects of prolonged steroid-based (cortisone) medications. One known human biochemical, taurine, synthesis of which occurs in the mammalian liver, and has demonstrated anti-inflammatory activity when administered centrally, but not when administered subcutaneously or interperitoneally. N-substituted derivatives of taurine include: 4-(2-Hydroxyethyl)-1-piperazine ethenesulfonic acid; C.sub.8 H.sub.18 N.sub.2 O.sub.4 S, which is commonly identified in the technical literature as HEPES (Merck Index, 12th edition monograph #4687). HEPES is available commercially from Angus Chemicals, as the sodium salt or, as the free acid. The scientific literature reports that intravenous injection of (14-C) HEPES, or of (3H) taurine, demonstrated rapid clearance, but with a significantly longer half-life compared with taurine. Mahon et al theorized that the greater anti-inflammatory effects of HEPES (sodium salt and the acid) compared with taurine, may be due to its slower systemic distribution or clearance, in vivo. The art suggest that HEPES is a significant agent to reduce cellular inflammation and cellular proliferation. However, the delivery systems for the HEPES treatment of inflammation remain to be optimized.
It is thus a principal object of this invention to provide a HEPES-based compound, an ester, and a pharmaceutical formulation including the ester, that is adapted for use in topically applied products to reduce symptoms of skin inflammation, wherein the particular etiology of the inflammation does not call for, or require, the use of antibiotics or germicidal compositions. The improved formulations for epidermal penetration, on bruises, muscle strains and sprains are also areas of useful treatment.
It is another object of the invention to combine the HEPES molecule with selected aliphatic acids, as the active ingredient of topical applications, which permit the HEPES moiety to penetrate the skin and so to better effect its anti-inflammatory nature.
It is a further object of the invention to provide a HEPES-containing active ingredient that is not limited to the known subcutaneous injection or IV infusion routes, but may also effective as a topical formulation.
A still further object of the invention is to provide HEPES esters as a cosmetic formulation ingredient, as a co-emulsifier, usable with topical analgesics.
Still another object of the invention is in a cosmetic preparation to incorporate an anti-skin ageing active ingredient.
These and other objects and benefits of this invention will become apparent from a study of the following specification.